Penn Researchers Call for New Paradigm in Clinical
Trials:
Individual Factors Must Be Considered When Designing and Interpreting
Clinical Trials

(Philadelphia, PA) - Two studies published this week from
the University of Pennsylvania School of Medicine point
to the need for a more individual approach to medicine and drug testing.
The two papers, from the lab of Garret FitzGerald, MD,
Director of Penn’s Institute for Translational Medicine and Therapeutics,
together with Penn colleagues Tilo Grosser MD, Research
Assistant Professor of Pharmacology, and Susanne Fries MD,
Research Associate in Pharmacology, highlight clinical studies involving
COX-2 inhibitors as an example.

The first study, published in the Journal of Clinical Investigation,
summarizes comprehensively the basic and clinical evidence that explains
how drugs like rofecoxib (VIOXX), celecoxib (CELEBREX), and valdecoxib
(BEXTRA) confer a small, but absolute, risk of heart attack and stroke.
The size of this risk is likely to be conditioned by the underlying risk
in a given patient of thrombosis and heart disease; the dose and duration
of action of a drug; and the duration of dosing and concurrent therapies,
such as low-dose aspirin.

The authors indicate how the clinical information from placebo-controlled
trials of the COX-2 inhibitors is congruent, both in outcome and in how
the information became manifest, with what would be expected from how
the drugs work pharmacologically to block the COX-2 enzyme. The authors
synthesize information from an understanding of drug mechanisms and epidemiology
to predict how traditional NSAIDs-drugs like diclofenac, ibuprofen, and
naproxen-may differ with respect to cardiovascular risk. Finally, they
synthesize this information to provide a rational basis for treating patients
with varied risk profiles as physicians await further information from
ongoing trials.

Lessons are drawn from the experience of the COX-2 inhibitors-particularly
the need to develop a more interdisciplinary approach to drug development
and monitoring of drug safety and how an emphasis on individualizing benefit
and risk can be used to refine the design of clinical trials.

The second paper, published in Gastroenterology, builds on the
theme of individualized therapy, demonstrating marked variation in individual
response to COX-2 inhibitors, as measured by plasma drug levels and the
degree of COX-2 inhibition within an individual. The researchers found
that a marked degree of variability in individuals dosed with either rofecoxib
or celecoxib, even when they studied apparently healthy, relatively young
individuals in a carefully controlled environment. This rigorous study
suggests that up to a third of the variability may reflect an individual's
genetics. Examples are given of variants in genes that affect either drug
metabolism or the COX enzymes themselves.

The study was conducted on 50 healthy volunteers between the ages of 21
and 43 years old who received a single dose of placebo, celecoxib and
rofecoxib in random order. This was done to allow researchers to compare
directly the responses to the drugs within the same subjects. Five of
the patients went thru the entire protocol 5 times to assess variability
within individuals. “A surprise of the study was that factors in
our environment result in varied response of the same individual to the
same dose of a drug, even when we try to standardize as many variables
as we can think of,” says Grosser.

Approximately 30 percent of the variability found in patients was attributable
to differences between individuals, suggesting the contribution of genetics
to a variety of biomarkers of drug response.

Fries, the first author of the Gastroenterology study, explains
that this work provides the impetus to develop a science-based approach
to risk management. “Exploitation of variability in response can
lead to tests which identify patients most likely to benefit or suffer
from drugs,” she says. “Our study provides a starting point
for the development of diagnostics that will let us conserve benefit while
managing the risk of COX-2 inhibitors.”

Such work heralds the rapidly emerging field of individualized medicine,
says FitzGerald. “This can guide both the design of future clinical
trials and the use of these drugs in practice.”

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